Objective:

Background:

E2086 is hypothesized to regulate the sleep/wake cycle by supporting wakefulness through the orexin neuronal pathway; its preclinical profile showed strong dose-dependent efficacy in promoting wakefulness and mitigating cataplexy. 

Design/Methods:

E2086-A001-101, a multicenter, randomized, double-blind, double-dummy, single-dose, N-of-1, 5-period crossover study, evaluated the efficacy, safety, and tolerability of E2086 (5 mg, 10 mg, 25 mg) compared with placebo (PBO) and modafinil 200 mg in adult participants with NT1. Male and female participants with verified diagnoses of NT1 were randomized to receive study drug within an hour of waketime following an overnight polysomnogram. Forty-minute maintenance of wakefulness tests (MWTs) were commenced 2 hours after waketime and continued every 2 hours until ~7 hours postdose (4 total). The Karolinska Sleepiness Scale (KSS) was administered at the end of each MWT. 

Results:

Twenty-two subjects were randomized; 19 subjects were completers (received all 5 treatments and had MWT efficacy data). Mean sleep latency (MSL) for E2086 was longer and statistically significant compared with PBO and modafinil. MSL with modafinil was also significantly longer versus PBO, establishing assay sensitivity. E2086 10 mg and 25 mg sustained wakefulness for ≥30 minutes; E2086 5 mg sustained wakefulness for >19 minutes throughout each MWT trial. The effect of E2086 on daytime alertness was durable, with participants maintaining significantly greater alertness with E2086 (all doses) versus PBO and with E2086 (10 mg and 25 mg doses) versus modafinil for each KSS assessment. E2086 was generally well tolerated, with most treatment-emergent adverse events being mild to moderate in severity. 

Conclusions:

These data demonstrate that E2086 has the potential to improve daytime wakefulness in patients with NT1. The efficacy/safety profile supports continued investigation of E2086 in the narcolepsy patient population.